Plasma metabolomic profiles enhance precision medicine for volunteers of normal health

Abstract

Precision medicine, taking account of human individuality in genes, environment, and lifestyle for early disease diagnosis and individualized therapy, has shown great promise to transform medical care. Nontargeted metabolomics, with the ability to detect broad classes of biochemicals, can provide a comprehensive functional phenotype integrating clinical phenotypes with genetic and nongenetic factors. To test the application of metabolomics in individual diagnosis, we conducted a metabolomics analysis on plasma samples collected from 80 volunteers of normal health with complete medical records and three-generation pedigrees. Using a broadspectrum metabolomics platform consisting of liquid chromatography and GC coupled with MS, we profiled nearly 600 metabolites covering 72 biochemical pathways in all major branches of biosynthesis, catabolism, gut microbiome activities, and xenobiotics. Statistical analysis revealed a considerable range of variation and potential metabolic abnormalities across the individuals in this cohort. Examination of the convergence of metabolomics profiles with whole-exon sequences (WESs) provided an effective approach to assess and interpret clinical significance of genetic mutations, as shown in a number of cases, including fructose intolerance, xanthinuria, and carnitine deficiency. Metabolic abnormalities consistent with early indications of diabetes, liver dysfunction, and disruption of gut microbiome homeostasis were identified in several volunteers. Additionally, diverse metabolic responses to medications among the volunteers may assist to identify therapeutic effects and sensitivity to toxicity. The results of this study demonstrate that metabolomics could be an effective approach to complement next generation sequencing (NGS) for disease risk analysis, disease monitoring, and drug management in our goal toward precision care.metabolomics | whole-exome sequencing | functional phenotyping | gene penetrance | disease assessment T he rapid progression of next generation sequencing (NGS) technology in recent years has significantly reduced the cost and time required to query a patient's genome accurately. The ability to comprehensively survey genetic variations and their associations with diseases is currently central to personalized medicine and can potentially transform clinical diagnosis and disease management. Indeed, whole-genome sequencing and whole-exome sequencing (WES) have been used successfully to investigate both common and rare diseases (1-7), as well as to provide guidance for drug treatment (8). Despite these successes, significant limitations remain on applying NGS in clinical settings for patient care (9-11). One of the key challenges is the proper interpretation of NGS data. It is known that human exome sequencing identifies ∼10,000 nonsynonymous single-nucleotide variants (12). The computational algorithms and databases for predicting and prioritizing functional pathogenic variants are not yet fully effective. More importantly, the impact of nongenetic factors, such ...

Metabolic features of chronic fatigue syndrome

“…Metabolomics has several advantages over genomics for the diagnosis of complex chronic disease and for the growing interest in precision medicine (5). First, fewer than 2,000 metabolites constitute the majority of the parent molecules in the blood that are used for cell-to-cell communication and metabolism, compared with 6 billion bases in the diploid human genome.…”

Effects of dietary sodium on metabolites: the Dietary Approaches to Stop Hypertension (DASH)–Sodium Feeding Study

“…4-Ethylphenylsulfate increased with sodium restriction and was the most strongly associated with change in sodium intake. This metabolite is produced by the gut microflora (11), and higher serum concentrations are associated with various health outcomes such as periodontal disease and lean body mass in animals or humans (12)(13)(14)(15)(16). 4-Ethylphenylsulfate is correlated with the consumption of soy products (17,18) and is elevated in the plasma of vegans compared with omnivores; a vegan diet increases concentrations of several products produced by the gut microbiota (19).…”

“…Others have suggested that both diet and the microbiome mediate associations between metabolites and blood pressure (23). Although speculative, the effect of sodium restriction on the gut microbiome may contribute to the increases in 4-ethylphenylsulfate and possibly to changes in other metabolites (e.g., 4-hydroxyphenylpyruvate, indole-related metabolites, and isovalerate) produced by gut bacterial metabolism (11).…”

8th Santorini Conference: Systems medicine and personalized health and therapy, Santorini, Greece, 3–5 October 2016

“…One way to go through the complexity of the data is by using metabolomics, able to precisely measure 2000 molecules in plasma. Metabolomics provides a real-time assessment of the phenotype, helps to unravel complex traits and to detect meaningful signals within the genome [7]. Novel technological innovations enable metabolomics to deliver signatures of disease and provide an integral tool for assessing mechanisms of drug action, thus expanding the boundaries of precision medicine and systems pharmacogenomics.…”